The results show that the peptide hypocretin-1 and the adenosine A1 receptor agonist SPA increase thermal antinociception when microinjected into the PnO. The hypocretin receptor-1 antagonist SB-334867 blocked the increase in thermal antinociception caused by hypocretin-1. These data suggest for the first time that within the PnO (), hypocretin receptor-1 may play a role in thermal antinociception. The findings are discussed in relation to adenosinergic and hypocretinergic modulation of pain and arousal states.
Adenosine is a neuromodulator formed during energy metabolism10
and PnO administration of adenosine agonists in rat25
increases sleep. Adenosine can also be antinociceptive11
and in the present study thermal antinociception was increased by PnO microinjection of the adenosine A1
receptor agonist SPA ( and ). These results are consistent with evidence that PnO microinjection of the adenosine A1
receptor agonist SPA into the pontine reticular formation of cat37
causes antinociception. The good agreement between data obtained from three species provides compelling support for the interpretation that adenosine receptors in brain regions known to regulate sleep/wake states, such as the pontine reticular formation, can also influence pain states.
Hypocretin-1 is a peptide synthesized by neurons in the lateral hypothalamus.34
Hypocretin-containing neurons project to multiple arousal-related brain regions, including the pontine reticular formation.31
Hypocretin-1 promotes wakefulness (reviewed in29
) and microinjection of hypocretin-1 into rat PnO increases wakefulness.42
The present results showing that PnO microinjection of hypocretin-1 is antinociceptive are consistent with a growing body of evidence that hypocretin-1 can alter pain transmission. For instance, microinjection of hypocretin-1 into rat posterior hypothalamus2
decreases responses to nociceptive input.
Hypocretin-1 has also been shown to cause antinociception during thermal,5, 27
and chemical5, 27
nociceptive stimuli in mouse and rat when administered intracerebroventricularly or intrathecally.27
In comparison to these reports, the present study found modest increases in antinociception. However, studies involving intrathecal or intracerebroventricular injections used doses of hypocretin-1 ranging from 30 pmol to 240 nmol.5, 27
One study showed that 30 pmol of hypocretin-1 caused a maximum %MPE of approximately 5%,5
which is similar to the current results obtained by microinjecting 10 pmol. The present finding of statistically significant antinociception due to a small percent change emphasizes the robustness of the drug effect. Hypocretin-1 is an endogenous neuropeptide and the statistically significant but modest increase in antinociception induced by PnO microinjection of hypocretin-1 may reflect tightly regulated hypocretinergic signaling within the brain. Synthetic agonists for hypocretin receptors may cause more efficacious antinociception.
Intrathecal7, 46, 47
administration of hypocretin-1 suppresses mechanical allodynia in rat models of postoperative,7
pain. Morphine also suppresses mechanical allodynia when administered systemically4, 12
in rat models of neuropathic pain. When morphine is given intrathecally, however, mechanical allodynia is not suppressed.4
The differences in suppression of mechanical allodynia due to intrathecal administration of hypocretin-1 or morphine may be due to the presence of hypocretin-19, 40
and its receptors17
in the spinal cord, as well as a possible reduction of spinal μ-opioid receptors resulting from neuropathic pain models.4
Even though hypocretin-1 and morphine have similar effects on mechanical allodynia when given intracerebroventricularly, these compounds have very different effects on arousal.
The reticular formation comprises a brainstem network that promotes the arousal and autonomic responses to nociceptive input.32
Although the reticular formation is not considered part of ascending pain pathways, it has been known for more than 10 years that areas of the reticular formation that regulate sleep can also alter nociception.20
Cholinomimetics administered to the PnO cause antinociception,20, 41
and microdialysis delivery of hypocretin-1 to rat PnO increases acetylcholine release in the PnO.3
The present results (; and ) provide the first evidence that hypocretin-1 administered to the PnO is antinociceptive.